DEUTERIUM-MODIFIED CFTR MODULATORS
This invention relates to novel 4,4,5,5,7,7-hexamethyl-5,7-dihydro-4H-thieno[2,3-c]pyranyl compounds, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering cystic fibrosis transmembrane conductance regulator (CFTR) modulators.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each R 1 is independently CH 3 , CDH 2 , CD 2 H, or CD 3 ;
each R 2 is independently CH 3 , CDH 2 , CD 2 H, or CD 3 ;
each R 3 is independently H or D;
Y is selected from
(i) a C 1-5 hydroxyalkyl optionally substituted by 0-10 deuterium,
(ii) a phenyl ring independently substituted by 0-5 deuterium and by 0-2 R 4 groups;
(iii) a C 3-6 cycloalkyl independently substituted by 0-11 deuterium and by 0-2 R 5 groups and 0-2 oxo groups, and
(iv) a 5- or 6-membered heteroaryl independently substituted by 0-4 deuterium and by 0-2 R 5 groups;
R 4 is halo, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy, wherein each alkyl or alkoxy group is optionally substituted with deuterium;
R 5 is halo, OH, —OC(═O)C 1-4 alkyl, —COOH, —C(═O)C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy, wherein each alkyl or alkoxy group is optionally substituted with deuterium;
provided that when each R 1 is CH 3 , each R 2 is CH 3 , each R 3 is H, R 4 , if present, is not substituted by deuterium, and R 5 , if present, is not substituted by deuterium, then Y is substituted by at least one deuterium.
2 . The compound of claim 1 , wherein the C 3-6 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein the C 3-6 cycloalkyl is substituted by 0-11 deuterium and 0-2 R 5 groups.
3 . The compound of claim 1 , wherein the 5- or 6-membered heteroaryl is selected from furanyl, thiophenyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidyl, or pyrazinyl, wherein the 5- or 6-membered heteroaryl are substituted by 0-2 R 5 groups.
4 . The compound of claim 1 , wherein:
each R 1 is independently CH 3 or CD 3 ;
each R 2 is independently CH 3 or CD 3 ; and
each R 3 is the same.
5 . The compound of claim 1 , wherein each R 1 is CD 3 , each R 2 is CD 3 , and each R 3 is H.
6 . The compound of claim 1 , wherein each R 1 is CD 3 , each R 2 is CD 3 , and each R 3 is D.
7 . The compound of claim 1 , wherein each R 1 is CH 3 , each R 2 is CH 3 , and each R 3 is D.
8 . The compound of claim 1 , wherein each R 1 is CH 3 , each R 2 is CD 3 , and each R 3 is D.
9 . The compound of claim 1 , wherein each R 1 is CH 3 , each R 2 is CD 3 , and each R 3 is H.
10 . The compound of claim 1 , wherein each R 1 is CD 3 , each R 2 is CH 3 , and each R 3 is D.
11 . The compound of claim 1 , wherein each R 1 is CD 3 , each R 2 is CH 3 , and each R 3 is H.
12 . The compound of claim 1 , wherein Y is pyrazolyl, cyclopropyl or phenyl, wherein the pyrazolyl and cyclopropyl are optionally substituted by 0-2 R 5 groups and the phenyl is optionally substituted by 0-2 R 4 groups.
13 . The compound of claim 1 , wherein R 4 is selected from halo and —OH.
14 . The compound of claim 1 , wherein R 5 is selected from halo, OH, C 1-4 alkyl, and C 1-4 haloalkyl, wherein each alkyl is optionally substituted with deuterium.
15 . The compound of claim 1 , wherein Y is:
16 . The compound of claim 1 , wherein Y is:
17 . The compound of claim 1 , where Y is phenyl, 2-hydroxyphenyl, or 2-hydroxy-4-fluorophenyl.
18 . The compound of claim 1 , where Y is 1-hydroxycyclopropyl, 1-hydroxymethyl-cyclopropyl, 1-hydroxy-2,2-dimethylpropyl, 1-hydroxy-2,2-dimethylethyl, 1-hydroxy-1-methylethyl, or 2-hydroxy-1,1-dimethylethyl.
19 . The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
20 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
21 . A method of treating cystic fibrosis in a subject comprising administering to the subject a compound of claim 1 .
22 . A method of treating chronic obstructive pulmonary disease (COPD) or Parkinson's disease in a subject comprising administering to the subject a compound of claim 1 .
23 . A method of treating a bile duct disorder or a kidney ion channel disorder in a subject comprising administering to the subject a compound of claim 1 .
24 . The method of claim 18 , wherein the kidney ion channel disorder is Bartter's syndrome or Dent's disease.